Cellular mechanisms of temporal lobe epilepsy in vitro studies in animal models

Abstract

Epilepsy is classically defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous activity in the brain . It is one of the most prevalent neurological disorder affecting over 50 million individuals worldwide, of which almost 80% are found in developing nations (WHO fact sheet, 2012). In India, over 10 million people have been estimated to suffer from Epilepsy. Apart from its severe debilitating effects, epilepsy also imposes a substantial economic burden with WHO estimating the cost of epilepsy care per person in India to almost 88% of the average income per capita. Temporal Lobe Epilepsy (TLE) is the most common and most medically refractory form of human epilepsy. In India, over 1 million people suffer from medically refractory epilepsy. Although surgical interventions have been adopted as an effective strategy to treat medically refractory epilepsy, less than 200 epilepsy surgeries are performed per year in India with over 500,000 potential candidates. This clearly depicts the magnitude of this problem in our country and highlights the lack of effective alternate treatment strategies. The primary aim of this thesis is to study the interactions between the CA3 and CA1 subfields of the hippocampus during epileptogenesis and gamma frequency synchronization using extracellular field potential recordings. To summarize our key findings, 1. Prolonged incubation in high [K+]o condition leads to the development of gamma bursts in CA1 which characteristically consists of spike discharges at 30-40Hz. 2. Anatomical and pharmacological isolation of CA1 increased the frequency at which gamma bursts occurred, thus showing the independent and highly rhythmic nature of these bursts. 3. Gamma bursts are primarily GABA-ergic in nature and are strongly attenuated by GABAA receptor blocker BMI. 4. Similar to BMI, application of oxytocin and bumetanide strongly attenuate the gamma bursts. These results suggest that a compromised Cl- homeostasis could possibly underlie gamma bursts generation.